Cyclosporin is a drug having immunosuppressant activity, which is used to prevent graft rejection in transplant patients and for the treatment of a series of autoimmune diseases characterized by an abnormal reaction of the immune system. The clinical availability of cyclosporin has greatly improved the prognosis of transplant patients, considerably increasing their survival. However, the drug has an intrinsic toxicity which limits its therapeutic window, requiring the achievement of defined plasma levels. Outside the therapeutic window the patient's life is threatened, both when plasma levels attained are lower than those needed—due to lack of efficacy and the consequent increased risk of rejection—and when plasma levels exceed the safe levels—due to the specific risk of toxicity, particularly renal and/or liver toxicity.
In its therapeutic use as an immunosuppressant, cyclosporin is currently administered either orally or by injection. However, since the solubility of cyclosporin in water is extremely low, (e.g. 20 μg/ml to 30 μg/ml), an oily solution containing ethanol has been recognized to be a suitable vehicle. Even so, the bioavailability of oral preparations of cyclosporin is extremely low, generally below 30%. This is believed to be due to the separation of cyclosporin as a solid immediately after it comes into contact with water, e.g. in the mouth and on contact with gastric fluids.
It is generally accepted that cyclosporin cannot be absorbed following oral administration unless it is first solubilized in gastrointestinal fluids by appropriate excipients.
The first cyclosporin formulations available for therapeutic use (SANDIMMUN®) were characterized by a high degree of intra- and interindividual variability with respect to absorption, so that it was necessary to frequently titrate the plasma levels in the individual patients in order to continuously adjust the administered dosage.
Subsequently, in order to avoid the described disadvantage, and thus to obtain less variable plasma levels of the drug, formulations that are based on preconcentrates for microemulsions and that have demonstrated less individual variability, or compositions that are difficult to produce and just as complex, were described. One of those formulations, (in the form of a preconcentrate for a microemulsion) was introduced onto the market (NEORAL®) as an improvement over the previous oily solution of cyclosporin in ethanol.
The prior art is rich in complex compositions which, nevertheless, lead to absorption profiles of the active ingredient which are extremely variable in quantitative terms.
U.S. Pat. No. 4,388,307, relating precisely to SANDIMMUN®, describes a cyclosporin-based composition containing (a) a non-ionic ester of a triglyceride and a polyalkylene polyol, (b) a saturated fatty acid triglyceride, and (c) a mono- or di-glyceride having improved physical and absorption properties.
U.S. Pat. No. 5,047,396 discloses an intravenous pharmaceutical formulation composed of a) 1 part by mass of one or more cyclosporins, b) 8 to 13 parts by mass of a monoester of a saturated hydroxylated fatty acid formed with polyethylene glycol or the mixture of said monoesters, c) 4 to 10 parts by mass of one or more intravenously administerable mono- or polivalent alcohols.
U.S. Pat. No. 5,756,450 discloses a combination of cyclosporin and a water soluble monoester of a saturated or unsaturated fatty acid and a polyol, especially a saccharide.
German patent application DE-4418115 discloses an at least ternary vehicle formed by the transesterification product of a vegetable oil and mono-, di- or triglyceride of oleic acid and/or linoleic acid, and/or of polyoxyethylenated vegetable oil, propylene glycol and ethanol.
U.S. Pat. No. 5,342,625, which relates to NEORAL®, describes a composition which allows a more homogeneous absorption of the active ingredient by means of a formulation which consists of a preconcentrate for microemulsion, that does not contain alkanols.
U.S. Pat. No. 5,639,724 discloses pharmaceutical compositions comprising a cyclosporin as active ingredient, a fatty acid triglyceride, a glycerol fatty acid partial ester or propylene glycol or sorbitol complete or partial ester, preferably, and a tenside having an HLB of at least 10, without ethanol.
U.S. Pat. No. 6,258,808 describes a composition containing a cyclosporin, 1,2-propylene glycol, a mixed mono-, di- and tri-glyceride and a hydrophilic surfactant.
U.S. Pat. No. 6,420,355 discloses a pharmaceutical composition in the form of an emulsion preconcentrate for oral administration and containing a cyclosporin. The pharmaceutical composition has a carrier medium for the cyclosporin that contains a hydrophilic organic solvent; a mixed mono-, di-, and tri-glyceride or a transesterified and polyethoxylated vegetable oil; and a polyoxyethylene-sorbitan-fatty acid ester surfactant.
U.S. Pat. No. 4,990,337 relates to a pharmaceutical composition comprising a cyclosporin in admixture with a monoglyceride or diglyceride of a C6-C10 fatty acid in an amount sufficient to dissolve the cyclosporin.
U.S. Pat. No. 5,589,455 discloses a microemulsion free from ethanol and containing (1) cyclosporin as the active ingredient; (2) polyethylene glycol having a molecular weight from 200 to 600 Da as cosurfactant; (3) a mixture comprising the esterification product of a fatty acid and a primary alcohol, the triglyceride of a medium-chain fatty acid nd the monoglyceride of a fatty acid; and (4) a surfactant having an HLB value from 10 to 17.
United States patent application US2002/0107183A1 describes a pharmaceutical composition containing (a) cyclosporin as the active ingredient, (b) an alkylene polyether and/or an alkylene polyester as vehicles, in which the HLB of component (b) is at least 10.
Pharmaceutical compositions containing water insoluble active ingredients are also disclosed in US2002120015, WO02/45696, WO00/37050, WO96/03113 and WO00/03753.